The present invention relates to a deazaguanine analog and particularly to a deazapurine compound for use as an inhibitor for 5xe2x80x2-deoxy-5xe2x80x2-methylthioadenosine phosphorylase (MTAP). The present invention also relates to pharmaceutical compositions comprising the composition of the present invention, as well as methods of using the compounds in inhibiting MTAP and in treating cancer in a mammal.
The present invention also relates to a method for producing the compounds of the present invention.
5xe2x80x2-deoxy-5xe2x80x2-methylthioadenosine phosphorylase (MTAP) catalyzes the reversible phosphorolysis of 5xe2x80x2-deoxy-5xe2x80x2-methylthioadenosine (MTA) to adenine and 5-methylthio-D-ribose-1-phosphate. MTA is a by-product of polyamine biosynthesis, which is essential for cell growth and proliferation. This salvage reaction is the principal source of free adenine in human cells. Because of its importance in coupling the purine salvage pathway to polyamine biosynthesis, MTAP is a potential chemotherapeutic target. The overall quaternary structure and subunit topology of MTAP are somewhat similar to mammalian purine nucleoside phosphorylase (PNP) (see Appleby, T. C., Erion, M. D., Ealick, S. E., Structure, 1999, 7, 629-641 for the crystal structure and a comparison to mammalian PNP).
Cancer cell lines lacking MTAP do display increased sensitivity towards known chemotherapeutic drugs such as methotrexate and azaserine in the presence of MTA, whereas cancer cell lines with MTAP activity are not as severely affected. In view of these observations, the treatment of MTAP+ tumors could be enhanced by the co-administration of a potent MTAP inhibitor together with traditional chemotherapeutic compounds that specifically target the de novo purine biosynthetic machinery.
Accordingly, it would be desirable to develop a potent MTAP inhibitor.
The present invention relates to certain derivatives of 9-deazaadenine and more particularly to 1-C-(9-deazaaden-9-yl)-1,4-imino-D-5xe2x80x2-deoxy-5xe2x80x2-methylthioribitol and pharmaceutically acceptable salts thereof.
Another aspect of the present invention relates to pharmaceutical compositions containing at least one of the above-disclosed compounds.
The present invention also relates to a method for suppressing 5xe2x80x2-deoxy-5xe2x80x2-methylthioadenosine phosphorylase in a patient by administering to the patient at least one of the above-disclosed compounds in an amount sufficient to suppress 5xe2x80x2-deoxy-5xe2x80x2-methylthioadenosine phosphorylase.
The present invention is also concerned with methods of using the compounds of the present invention in treating cancer in a mammal.
A still further aspect of the present invention is concerned with a method for preparing the above-disclosed compounds. The process comprises:
a) cyanomethylating 5-O-t-butyldimethylsilyl-1, N-dehydro-1,4-dideoxy-1,4-imino-2,3-O-isopropylidene-D-ribitol with the anion of acetonitrile;
b) forming the corresponding pyrrole;
c) cyclizing the pyrrole from b) with formamidine acetate to form the corresponding hypoxanthine;
d) deprotecting the hypoxanthine prepared in c);
e) acetylating the compound prepared in d) with acetic anhydride in pyridine to provide the corresponding tri-O-acetate;
f) chlorinating the tri-O-acetate from e) to provide the corresponding 6-chloro compound;
g) forming the corresponding adenine compound by ammonolysis of the 6-chloro compound;
h) selectively tosylating the 5xe2x80x2-hydroxyl with tosyl chloride to form the corresponding 5xe2x80x2-O-tosyl compound; and
i) displacing the 5xe2x80x2-O-tosyl group with thiomethoxide to provide the desired compound.
Still other objects and advantages of the present invention will become readily apparent by those skilled in the art from the following detailed description, wherein it is shown and described preferred embodiments of the invention, simply by way of illustration of the best mode contemplated of carrying out the invention. As will be realized the invention is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, without departing from the invention. Accordingly, the description is to be regarded as illustrative in nature and not as restrictive.